A number of studies carried out over the recent years in populations with different ethnic backgrounds outline a role for genetic factors in the progression of benign non-alcoholic fatty liver disease (NAFLD) to non-alcoholic hepatosteatitis (NASH). However, the role of environmental factors, such as an increase in dietary fat intake, in the development of steatosis, inflammation, fibrosis, cirrhosis, and hepatocellular cancer development of NAFLD are unresolved.
To determine genotype-independent pathophysiological changes in initial NAFLD stages that may mediate the progression of benign hepatosteatosis, Melanie Kahle and colleagues from the Helmholtz Center Munich in the German Mouse Clinic carried out studies in the four genetically heterogenous mouse strains C3HeB/FeJ, C57BL/6NTac, C57BL/6J, and 129P2/OlaHsd males. To induce mild hepatosteatosis males were subjected to a 7, 14 or 21 day high-fat-diet challenge and physiological responses during and gene expression patterns in liver following 21 days of high-fat diet challenge determined.
In all strains high-fat-diet exposure increased body mass, whole body fat mass, epididymal white adipose tissue mass, as well as plasma high densitiy lipoprotein and total cholesterol concentrations compared to littermates fed low-fat-diet. Development of moderate obesity caused by high-fat-diet intervention was paralleled by mild hepatic steatosis, however extent and progression patterns markedly differed between the mouse strain. “Universal” adaptations in transcript signatures and transcription factor regulation in liver outline an early increase in the organ's vulnerability to oxidative stress damage what could advance hepatosteatosis to steatohepatitis. Besides strain specific responses, the scientists identified genetic background-independent alterations in gene expression signatures pointing out novel candidates that potentially link the development of human NAFLD with type 2 diabetes mellitus, cancer, and thyroid hormone metabolism.
An increase in dietary lipid intake and development of moderate obesity mediates changes in gene expression patterns that link insulin resistance, type 2 diabetes mellitus, cancer, and thyroid hormone metabolism with hepatosteatosis, hence, facilitating the search for novel molecular mechanisms potentially implicated in the pathogenesis of human NAFLD.
Phenotypic comparison of common mouse strains developing high-fat diet-induced hepatosteatosis, Kahle et al., 2013, MOLECULAR METABOLISM (2013) 435–446, doi: http://dx.doi.org/10.1016/j.molmet.2013.07.009